Prognostic value of <i>TP53</i> mutation status in metastatic triple-negative and hormone receptor-positive breast cancer using cell-free DNA genomic profiling.
Authors: Daria Seriak, Arielle J Medford, Andrzej Niemierko, Aditya Bardia, Jennifer C. Keenan, Steven J. Isakoff, Seth Andrew Wander, Laura Spring, Beverly Moy, Neelima Vidula, Leif W. Ellisen, Massimo Cristofanilli, Andrew A. Davis, Katherine Clifton, Whitney L Hensing, Ami N. Shah, Lorenzo Gerratana
Journal: Journal of Clinical Oncology (2023)

e13099 Background: TP53 is one of the most frequently mutated genes in metastatic breast cancer (MBC); however, its prognostic role remains undetermined. Plasma-based genotyping via cell-free DNA (cfDNA) is a noninvasive means of assessing the genomic landscape of MBC, accounting for heterogeneity between tumors. This study evaluated the association between TP53 alterations detected via cfDNA and clinical outcomes among patients with hormone receptor-positive HER2-negative breast cancer (HR+/HER2- BC) and triple-negative breast cancer (TNBC) in a metastatic setting. Methods: cfDNA analyses were performed on plasma samples collected from patients with TNBC and HR+/HER2- BC treated at the Massachusetts General Hospital Cancer Center and Washington University in St Louis using Guardant360, a 74-gene cfDNA sequencing assay. Progression-free survival (PFS) and overall survival (OS) were compared based on TP53 alteration status in cfDNA. Multivariable Cox regression was performed adjusting for age, de novo metastases, number of prior treatments, and immunotherapy. Results: TP53 alterations were found in 187 out of 540 patients with HR+/HER2- BC (34.6%) and 87 out of 117 patients with TNBC (74.4%). The most frequent co-existing mutations with TP53 mutations in TNBC were PIK3CA (27.6%), EGFR (26.4%), and CCNE1 (20.7%). For HR+/HER2- BC, the top co-existing mutations were PIK3CA (51.3%), ESR1 (30.5%), and EGFR (21.9%). Median PFS for patients with TNBC with and without TP53 mutations was 6.8 and 6.5 months, respectively (HR = 1.1, 95% CI 0.6-2.0, p = 0.66). Median OS for patients with TNBC with TP53 mutations was 14.2 months, whereas patients without TP53 mutations did not reach median OS (HR = 2.0, 95% CI 0.9-4.1, p = 0.08). Median PFS and OS for patients with HR+/HER2- BC were stratified by the type of therapy initiated immediately after cfDNA testing. Median PFS for patients who received endocrine therapy with and without TP53 mutations was 13.1 vs. 15.9 months, respectively (HR = 1.1, 95% CI 0.7-1.6, p = 0.78). Median OS with and without TP53 mutations was 40.6 vs. 55.8 months, respectively (HR = 1.4, 95% CI 0.8-2.3, p = 0.25). For patients with HR+/HER2- BC who received non-endocrine-based therapy following cfDNA testing, median PFS was 4.2 vs 5.6 months for those with and without TP53 mutations, respectively (HR = 1.0, 95% CI 0.6-1.7, p = 0.92). Median OS for those with TP53 mutations was 9.9 months and 17.1 months for those without (HR = 1.8, 95% CI 1-3.3, p = 0.05). Conclusions: TP53 alterations were detectable via cfDNA in patients with metastatic HR+/HER2- BC and TNBC and were associated with poor survival suggesting a potential prognostic role. The analysis did not filter out potential clonal hematopoiesis, a limitation of the study. Further study is warranted to determine the association of these mutations with outcomes in the setting of specific treatment regimens.